This group works on gene regulation in the immune system. Our focus has been to elucidate the role of two transcription factors, RXR- and ICSBP. RXR- is a member of the large nuclear hormone receptor superfamily. It is capable of heterodimerizing with other receptors is involved in ligand dependent transcription. ICSBP is a member of the interferon regulatory factor (IRF) family and plays a role in gene regulation mediated by interferons and viruses. We have studied what role RXR plays, forming a heterodimer with RAR in retinoid mediated gene regulation. Synthetic retinoids that are specific for RAR and RXR have been tested for transcriptional activity of heterodimers. We found that RAR ligands (but not RXR ligands) stimulate transcription. Although an RXR ligand alone was not active in stimulating transcription when it was added together with an RAR ligand strong synergistic activation was noted. The co-administration of the two ligands led to synergistic enhancement of biological activity in P19 cells, as neuronal differentiation and apoptosis were both dramatically increased. Similarly increased teratogenic effect was seen in frog and zebrafish development by the two ligands. In vivo footprinting analysis showed that the RXR ligand although itself did not induce the receptor heterodimer occupancy at the RARE, a combination with an RAR ligand stabilized occupancy. These and data obtained previously in this laboratory show that RXR is an active partner of the heterodimer, and participate in transcription. The in vivo function of ICSBP was studied using ICSBP-/- mice. these mice present a striking abnormality in that myeloid cells are markedly increased in bone marrow, spleen and lymph nodes even from an early stage. The myeloid cells in ICSBP-/- mice are mostly GR-1+/MacI+ cells, and are morphologically typical granulocytes. Cytokine gene expression was examined with quantitative RT-PCR, which showed that while IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, TNF and CSFs are expressed normally expression of IL-12 was markedly reduced in ICSBP-/- mice. IL-12 is a "master" cytokine produced in activated macrophages, and is shown to control expression of IFN- in TH1 cells. As a results of defective IL-12 production ICSBP-/- mice are defective in expressing IFN-, a cytokine with anti-viral and bactericidal activities, that also stimulates T cell mediated immune responses. Taken together our results indicate that ICSBP plays a critical role in host defense.